Daytime napping after a night of sleep loss decreases sleepiness, improves performance, and causes beneficial changes in cortisol and interleukin-6 secretion.
Sleep loss has been associated with increased sleepiness, decreased performance, elevations in inflammatory cytokines, and insulin resistance. Daytime napping has been promoted as a countermeasure to sleep loss. To assess the effects of a 2-h midafternoon nap following a night of sleep loss on postnap sleepiness, performance, cortisol, and IL-6, 41 young healthy individuals (20 men, 21 women) participated in a 7-day sleep deprivation experiment (4 consecutive nights followed by a night of sleep loss and 2 recovery nights). One-half of the subjects were randomly assigned to take a midafternoon nap (1400-1600) the day following the night of total sleep loss. Serial 24-h blood sampling, multiple sleep latency test (MSLT), subjective levels of sleepiness, and psychomotor vigilance task (PVT) were completed on the fourth (predeprivation) and sixth days (postdeprivation). During the nap, subjects had a significant drop in cortisol and IL-6 levels (P < 0.05). After the nap they experienced significantly less sleepiness (MSLT and subjective, P < 0.05) and a smaller improvement on the PVT (P < 0.1). At that time, they had a significant transient increase in their cortisol levels (P < 0.05). In contrast, the levels of IL-6 tended to remain decreased for approximately 8 h (P = 0.1). We conclude that a 2-h midafternoon nap improves alertness, and to a lesser degree performance, and reverses the effects of one night of sleep loss on cortisol and IL-6. The redistribution of cortisol secretion and the prolonged suppression of IL-6 secretion are beneficial, as they improve alertness and performance.


Variability in the origin of the obturator artery.
General surgeons dealing with laparoscopic herniorrhaphy should be aware of the aberrant obturator artery that crosses the superior pubic ramus and is susceptible to injuries during dissection of the Bogros space and mesh stapling onto Cooper's ligament. The obturator artery is usually described as a branch of the anterior division of the internal iliac artery, although variations have been reported. The present study was conducted on 98 pelvic halves of embalmed cadavers, and the origin and course of the obturator artery were traced and noted. In 79% of the specimens, the obturator artery was a branch of the internal iliac artery. It branched off at different levels either from the anterior division or posterior division, individually or with other named branches. In 19% of the cases, the obturator artery branched off from the external iliac artery as a separate branch or with the inferior epigastric artery. However, in the remaining 2% of the specimens, both the internal and the external iliac arteries branched to form an anastomotic structure within the pelvic cavity. The data obtained in this study show that it is more common to find an abnormal obturator artery than was reported previously, and this observation has implications for pelvic surgeons and is of academic interest to anatomists. Surgeons dealing with direct, indirect, femoral, or obturator hernias need to be aware of these variations and their close proximity to the femoral ring.


The Effect of a High-Dose Vitamin B Multivitamin Supplement on the Relationship between Brain Metabolism and Blood Biomarkers of Oxidative Stress: A Randomized Control Trial.
A diet rich in B-group vitamins is essential for optimal body and brain function, and insufficient amounts of such vitamins have been associated with higher levels of neural inflammation and oxidative stress, as marked by increased blood plasma homocysteine. Neural biomarkers of oxidative stress quantified through proton magnetic spectroscopy (1H-MRS) are not well understood, and the relationship between such neural and blood biomarkers is seldom studied. The current study addresses this gap by investigating the direct effect of 6-month high-dose B-group vitamin supplementation on neural and blood biomarkers of metabolism. Using a randomized, double-blind, placebo-controlled design, 32 healthy adults (20 female, 12 male) aged 30⁻65 years underwent blood tests (vitamin B6, vitamin B12, folate, and homocysteine levels) and 1H-MRS of the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) before and after supplementation. Results confirmed the supplement was effective in increasing vitamin B6 and vitamin B12 levels and reducing homocysteine, whereas there was no change in folate levels. There were significant relationships between vitamin B6 and N-acetylaspartate (NAA), choline, and creatine, as well as between vitamin B12 and creatine (ps < 0.05), whereas NAA in the PCC increased, albeit not significantly (p > 0.05). Together these data provide preliminary evidence for the efficacy of high-dose B-group supplementation in reducing oxidative stress and inflammation through increasing oxidative metabolism. It may also promote myelination, cellular metabolism, and energy storage.


Autophagy is activated for cell survival after endoplasmic reticulum stress.
Eukaryotic cells deal with accumulation of unfolded proteins in the endoplasmic reticulum (ER) by the unfolded protein response, involving the induction of molecular chaperones, translational attenuation, and ER-associated degradation, to prevent cell death. Here, we found that the autophagy system is activated as a novel signaling pathway in response to ER stress. Treatment of SK-N-SH neuroblastoma cells with ER stressors markedly induced the formation of autophagosomes, which were recognized at the ultrastructural level. The formation of green fluorescent protein (GFP)-LC3-labeled structures (GFP-LC3 "dots"), representing autophagosomes, was extensively induced in cells exposed to ER stress with conversion from LC3-I to LC3-II. In IRE1-deficient cells or cells treated with c-Jun N-terminal kinase (JNK) inhibitor, the autophagy induced by ER stress was inhibited, indicating that the IRE1-JNK pathway is required for autophagy activation after ER stress. In contrast, PERK-deficient cells and ATF6 knockdown cells showed that autophagy was induced after ER stress in a manner similar to the wild-type cells. Disturbance of autophagy rendered cells vulnerable to ER stress, suggesting that autophagy plays important roles in cell survival after ER stress.


A genetically retargeted adenoviral vector enhances viral transduction in esophageal carcinoma cell lines and primary cultured esophageal resection specimens.
To evaluate if an integrin-retargeted adenoviral vector could establish a more efficient and tumor-specific gene transfer in esophageal carcinoma cells. Although preclinical data indicated that adenoviral gene therapy could be a promising novel treatment modality for various malignancies, clinical results are often disappointing. An important problem is the decreased tumoral expression of the Coxsackie and adenovirus receptor (CAR), which mediates adenoviral entry. Retargeting the adenoviral vector to other cellular receptors, by inserting an arginine-glycine-aspartate (RGD) tripeptide in the fiber knob, might overcome this problem. Four esophageal carcinoma cell lines and 10 fresh surgical resection specimens were cultured. All were infected with the native adenovirus (Ad) and the retargeted adenovirus (AdRGD), encoding for the reporter genes luciferase or Green Fluorescent Protein to analyze gene transfer efficiency. In all cell lines, an increase in viral expression per cell and an increase in the percentage of transduced cells were seen with the retargeted adenovirus. Also, in the primary cultures of carcinoma cells, a more efficient gene transfer was seen when the retargeted vector was used. This phenomenon was less pronounced in normal cells, indicating that the RGD virus transduces tumor cells more efficiently than normal cells. This study demonstrates that an RGD retargeted adenovirus infects human esophageal carcinoma cells with enhanced efficiency, while in normal esophageal cells this effect is less pronounced. Therefore, this retargeted vector is expected to have a better performance in vivo, when compared with nonretargeted vectors used for cancer gene therapy so far.


Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.
Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization. We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response. Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed. Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov.


Orfelia-type luciferin and its associated storage protein in the non-luminescent cave worm Neoditomyia sp. (Diptera: Keroplatidae) from the Atlantic rainforest: biological and evolutionary implications.
Bioluminescence in Diptera is found in the family Keroplatidae, in the glowworms of the genera Arachnocampa, Orfelia and Keroplatus. Despite belonging to the same family, Arachnocampa spp. and Orfelia fultoni display morphologically and biochemically distinct bioluminescence systems: Arachnocampa spp. produce light by the terminal ends of Malpighian tubules using ATP, a luciferin and a luciferase, whereas Orfelia fultoni produces light by translucent areas associated with rows of black bodies in the anterior and posterior parts of the body, using a 140 kDa luciferase and a luciferin which do not cross-react with the Arachnocampa luciferin-luciferase system, and a substrate binding fraction (SBF) which apparently releases luciferin in the presence of reductants. While several other keroplatids are not luminescent, we recently discovered a non-luminescent web-constructing keroplatid larva living in the roofs of caves in the Atlantic rainforest in Brazil, which noteworthily has a compound with Orfelia luciferin-like activity and its associated binding protein (SBF). Both the Neoditomyia luciferin-like compound and SBF cross-react with purified Orfelia luciferase to produce light in the same blue region of the Orfelia luciferin-luciferase system (479 nm). We also checked for the presence of Orfelia-type luciferin in Arachnocampa luminosa and Aedes aegytpi larval bodies, but no traces were found. Molecular studies indicate that Neoditomyia sp. is phylogenetically closer to Keroplatus and Orfelia than to Arachnocampa species. The presence of luciferin and its associated binding protein in this non-bioluminescent keroplatid larva indicates that luciferin may display another important biochemical function in keroplatid larvae and suggests that bioluminescence could be a recently evolved trait in Keroplatidae.


Correlation of Ocular Biometric Parameters and Macular Ganglion Cell Layer in Normal Eyes.
To determine the association between ocular biometric parameters and macular ganglion cell layer (MGCL) thickness in normal eyes. This observational cohort study was conducted with 76 eyes of 76 healthy subjects. Keratometry, pachymetry, corneal volume, iridocorneal angle were measured with Sirius (CSO, Florence, Italy); axial length, anterior chamber depth, anterior chamber volume, corneal diameter were measured with IOL Master (Carl Zeiss Meditec, Dublin, California). For all participants, serial horizontal Spectralis Domain Optical Coherence Tomography (SD-OCT, Heidelberg Engineering, GmbH, Dossenheim, Germany) scans of the macula and peripapillary retinal nerve fiber layer (RNFL) analysis were obtained using SD-OCT. The relationship between numerical variables was given by Pearson correlation coefficient. The mean age of the subjects was 36.3 ± 11.9 years (between 19 and 70 y). Fifty-one patients were female (67.1%) and twenty-five patients were male (32.9%). MGCL was found to be correlated with anterior chamber depth, anterior chamber volume, iridocorneal angle, axial length and white to white (p = .015 r = 0.594, p = .002 r = 0.365, p = .013 r = 0.299, p = .004 r = 0.335, p = .013 r = 0.289, respectively). In addition, MGCL was correlated positively with the mean global and superotemporal RNFL (p ≤ 0.005). However, neither central corneal thickness nor keratometry values were found to be correlated with MGCL. The results of this study showed that MGCL thickness is affected by ocular biometric parameters. Therefore, these parameters should be taken into consideration when interpreting MGCL thickness measurements in the diagnosis of glaucoma.


Alternative models of cardiac rehabilitation: a systematic review.
The traditional hospital-based model of cardiac rehabilitation faces substantial challenges, such as cost and accessibility. These challenges have led to the development of alternative models of cardiac rehabilitation in recent years. The aim of this study was to identify and critique evidence for the effectiveness of these alternative models. A total of 22 databases were searched to identify quantitative studies or systematic reviews of quantitative studies regarding the effectiveness of alternative models of cardiac rehabilitation. Included studies were appraised using a Critical Appraisal Skills Programme tool and the National Health and Medical Research Council's designations for Level of Evidence. The 83 included articles described interventions in the following broad categories of alternative models of care: multifactorial individualized telehealth, internet based, telehealth focused on exercise, telehealth focused on recovery, community- or home-based, and complementary therapies. Multifactorial individualized telehealth and community- or home-based cardiac rehabilitation are effective alternative models of cardiac rehabilitation, as they have produced similar reductions in cardiovascular disease risk factors compared with hospital-based programmes. While further research is required to address the paucity of data available regarding the effectiveness of alternative models of cardiac rehabilitation in rural, remote, and culturally and linguistically diverse populations, our review indicates there is no need to rely on hospital-based strategies alone to deliver effective cardiac rehabilitation. Local healthcare systems should strive to integrate alternative models of cardiac rehabilitation, such as brief telehealth interventions tailored to individual's risk factor profiles as well as community- or home-based programmes, in order to ensure there are choices available for patients that best fit their needs, risk factor profile, and preferences.


Electroformation of phospholipid giant unilamellar vesicles in physiological phosphate buffer.
Phospholipid Giant Unilamellar Vesicles (GUVs) are usually prepared by electroformation in water, that is in a low-conductivity solution. We developed a protocol allowing their electroformation in the most common physiological buffer, phosphate-buffered saline (PBS). This was achieved based on a specific sequence of increasing electrical fields and for the two usual electrode types for electroformation, namely Indium Tin oxide-coated glass slides and Pt electrodes. These GUVs are stable over time (hour time-scale) and they can be isolated or micro-injected. The membrane composition was modified by adding cholesterol in order to adjust its mechanical properties. The optimal proportion of cholesterol vs. total phospholipid concentration was a ratio of 20 mol%, which increases membrane rigidity and facilitates vesicle microinjection.


Emergency contraception: knowledge and attitudes of family physicians of a teaching hospital, Karachi, Pakistan.
This study was conducted to assess the knowledge of family medicine providers and their attitudes towards emergency contraception in a teaching hospital in Karachi, Pakistan. A 21-item questionnaire containing the demographic profile of respondents and questions concerning knowledge of and attitudes towards emergency contraception was distributed among participants. In total, 45 interviews were conducted, with a response rate of 100%, with faculty physicians (33%), residents (27%), medical officers (40%), 36% male and 64% female physicians; of them, the majority (64%) were married. Although the large majority (71%) of the respondents reported considerable familiarity with emergency contraception, objective assessment revealed deficiencies in their knowledge. About 38% of the participants incorrectly chose menstrual irregularity as the most common side-effect of progestin-only emergency contraception pills, and only 33% answered that emergency contraception was not an abortifacient while 42% were unsure. Forty percent of the physicians prescribed emergency contraception in the past. The large majority (71%) of the physicians were familiar with emergency contraception, yet deficiencies in knowledge inaccuracies were identified. Barriers to its use were identified as 'it will promote promiscuity' (31%), religious/ethical reasons (27%), liability (40%), teratogenicity (44%), and inexperience (40%). Overall attitudes regarding emergency contraception were positive; however, most (82%) physicians were unsatisfied with their current knowledge of emergency contraception, and there was a discrepancy between perceptions of physicians and actual knowledge. Interventions providing education to family physicians regarding emergency contraception is strongly recommended.


[Metabolic side effects of risperidone in early onset schizophrenia].
Atypical antipsychotics have a favourable risk/benefit profile in early onset schizophrenia (EOS). However, despite increasing use of psychotropic medication in children and adolescents, their endocrine and metabolic side-effects (weight gain, obesity, and related metabolic abnormalities such as hyperglycaemia and dyslipidemia) are of particular concern, especially within this paediatric population that appears to be at greater risk as compared with adults for antipsychotic-induced metabolic adverse effects. In addition to medication, many factors contribute to weigh gain in psychiatric patients, including sedentary lifestyle and poor diet. Excessive weigh gain has several deleterious effects in psychiatric patients, including stigmatization and further social withdrawal, and non compliance with medication. Furthermore, excessive corpulence may evolve to a metabolic syndrome with a high-risk state for future cardiovascular morbidity and mortality in adult age. Because youths are still developing at the time of psychotropic drug exposure, in a context of physiological changes in hormonal and endocrines levels and body composition, most reference values need to be adjusted for gender, age and growth charts. Hence, sex- and age-adjusted BMI percentiles and BMI Z scores are crucial to assess weight gain in children and adolescents. Obesity thresholds have been proposed to define "at risk" categories of patients. In recently issued guidelines, thresholds for antipsychotic-induced weight gain in adults have been set at a 5% increase or one point increase in BMI unit. To date, no definition has reached a consensus in childhood and adolescence. However, some at risk states requiring action are proposed in literature: more than 5% increase in weight within a three-month period; more than half a point increase in BMI Z score; between 85th and 95th BMI percentile plus one adverse health consequence (i.e. hyperglycaemia, dyslipidemia, hyperinsulinemia, hypertension, or orthopaedic, gallbladder, or sleep disorder); or more than 95th BMI percentile or abdominal obesity (i.e. abdominal circumference above 90th percentile). As a matter of fact, numerous studies that have assessed weight gain during antipsychotic treatment are clearly limited, either because of their short duration (a few weeks), or because of their methodology: indeed, only weight gain is generally reported as an assessment tool. Merely noting an increase in body weight over time does not in itself signify a problem, and may underscore the importance of excessive corpulence growth as compared with controls. Adjusted BMI percentiles and BMI Z scores were calculated in only a few studies. This pilot study focuses on the metabolic effects of risperidone in children and adolescents up to 16 years of age. This study is part of a larger, regional study on metabolic side effects of antipsychotic medication in adults, promoted by the university hospital centre in Lille, France. Patients included in the study were referred to our department of child and adolescent psychiatry for EOS (K-SADS). They had received no antipsychotic treatment prior to their inclusion. Weight, height, sex- and age-related BMI percentiles and BMI Z scores, waist circumference, blood pressure, fasting triglyceride levels, fasting total and high-density lipoprotein cholesterol levels, and fasting glucose level were measured at M0, M3, and M6. BMI, sex- and age-related BMI percentiles and adjusted BMI Z scores were obtained from tables and calculator (www.kidsnutrition.org). Twenty-six children and adolescents (21 males, five females) aged 7 to 15.5 years (mean=12.9 years, sd=2.3) were included. They all received a diagnosis of schizophrenia according to the schedule for affective disorders and schizophrenia for school-aged children (K-SADS). They all received risperidone from 1mg/day to a maximum of 6 mg/day. Statistical analysis principally shows a significant link between prescription of risperidone in EOS and six-months increases of BMI (increase of 4.7 kg/m(2), p<0.0001), sex- and age-adjusted BMI percentile (increase of 29.3 points, p<0.0025), and BMI Z scores (increase of 1.1 point, p<0.0001). No patient showed metabolic syndrome, but one girl presented with a 1g/l increase of fasting total cholesterol at two-months. Despite the limited number of children included, our results confirm a strong link between prescription of risperidone in EOS and risk of obesity. Clinicians and caregivers need to be aware of the potential endocrine and metabolic adverse effects of atypical antipsychotics, and systematically ask for family history of metabolic disorder, life style, diet and habits. With adolescents, the sole monitoring of weight gain, and even of BMI, underestimates the gain of corpulence. One methodological implication of our study is that adjusted BMI Z scores are the best-suited measure to assess long-term drug-induced weight gain in comparison to developmental changes. Alternative treatment should be considered in some cases. Other antipsychotics, like aripiprazole, may have a better benefit/risk ratio and then may be prescribed as a first prescription or as a switch. Associations of antipsychotics may also be of interest but we lack controlled studies in children and adolescents. In some cases, alternative treatments like repetitive trans-cranial magnetic stimulations (rTMS) may be required. Their efficacy and their place in the therapeutic strategy of pharmacoresistant schizophrenia in children and adolescents have to be assessed in regard to metabolic and blood side effects of clozapine.


Mitochondrial peroxidase TPx-2 is not essential in the blood and insect stages of Plasmodium berghei.
Malaria parasites actively proliferate in the body of their vertebrate and insect hosts, and are subjected to the toxic effects of reactive oxygen species. The antioxidant defenses of malaria parasites are considered to play essential roles in their survival and are thus considered promising targets for intervention. We sought to identify the cellular function of thioredoxin peroxidase-2 (TPx-2), which is expressed in the mitochondria, by disrupting the TPx-2 gene (pbtpx-2) of the rodent malaria parasite Plasmodium berghei. In three independent experiments, two disruptant populations (TPx-2 KO) and three wild-type parasite populations with pyrimethamine resistance (dhfr-ts/mt at the DHFR-TS locus) and intact pbtpx-2 (TPx-2 WT) were obtained and cloned. Null expression of TPx-2 in the KO population was confirmed by RT-PCR and Western blot analyses. The TPx-2 KO parasite developed normally in mouse erythrocytes and multiplied at a rate similar to that of the TPx-2 WT parasite during the experimental period. The peak period of gametocytemia was delayed by 1 day in the TPx-2 KO compared with that of the TPx-2 WT and the parent parasite, however, the highest gametocyte number was comparable. The number of midgut oocysts in the TPx-2 KO at 14 days post feeding was comparable to that of the TPx-2 WT. The present finding suggests that mitochondrial Prx TPx-2 is not essential for asexual and the insect stage development of the malaria parasite.


Immunogenicity and safety of MMRV and PCV-7 administered concomitantly in healthy children.
We assessed the immunogenicity and safety of a combination measles, mump, rubella, and varicella vaccine (MMRV) (ProQuad [Merck & Co, Inc, West Point, PA]) administered to healthy children concomitantly with a pneumococcal 7-valent conjugate vaccine (PCV-7) (Prevnar [Pfizer, Philadelphia, PA]). Healthy 12- to 15-month-old children who lacked vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster but had written documentation of receipt of a 3-dose primary series of PCV-7 were randomly assigned in a 2:1:1 ratio to receive either the MMRV and PCV-7 (group 1), PCV-7 followed 6 weeks later by MMRV (group 2), or MMRV followed 6 weeks later by PCV-7 (group 3). The primary safety analysis was 56 days (28 days after each visit). Immunogenicity was evaluated 6 weeks after each vaccination. A total of 1027 children were enrolled (group 1: 510; group 2: 258; group 3: 259). For all 3 groups, the antibody response rate was ≥96.8% for measles, mumps, and rubella, ≥88.0% for varicella-zoster virus, and ≥98.3% for all of the 7 Streptococcus pneumoniae serotypes. The immune responses to all antigens present in MMRV and PCV-7 were similar whether administered concomitantly or sequentially. The incidence of local and systemic adverse experiences (AEs) was comparable between group 1 and groups 2 and 3 combined. No vaccine-related serious AEs were reported. Concomitant administration of the MMRV and PCV-7 is highly immunogenic and generally well tolerated. Similar immune responses between the groups support concomitant administration of the MMRV and PCV-7 to healthy children 12 to 15 months of age.


Morphometrical characteristics of age-associated changes in the thymus of old male Wistar rats.
In order to provide a morphometrical description of the changes in the aged rat thymus and to relate them to apoptotic and proliferative activity of thymocytes, the thymuses from 3- and 18-month-old male Wistar rats and the percentages of bromodeoxyuridine-incorporating and apoptotic cells in cultures of thymocytes were assessed by stereological analysis and flow cytometry, respectively. In old rats the volume of lymphoepithelial thymic tissue is markedly reduced, reflecting a sharp decrease in the total number of thymocytes. A reduction in the proliferative capacity of thymocytes and increase in their susceptibility to apoptosis are, most likely, primarily responsible for a 7-fold reduction in thymic cellularity in old animals. Furthermore, only the volume of cortical compartment was affected by aging, while that of medulla, despite of reduced cellularity, was not significantly altered. The loss of functional tissue in aged thymus is compensated by a substantial increase in the volume of inter-lobular connective and adipose tissue, so the thymic weight remained unaltered in old rats. These results suggest that thymus of aged Wistar rats exhibits morphological characteristics similar to those found in aged human thymus and thus may serve as an animal model for further investigations of thymus-related changes in immunological aging.


Transgenic expression of full-length 2',5'-oligoadenylate synthetase 1b confers to BALB/c mice resistance against West Nile virus-induced encephalitis.
Susceptibility of inbred strains to infection with West Nile virus (WNV) has been genetically associated with an arginine-to-a nonsense codon substitution at position 253 (R253X) in the predicted sequence of the murine 2',5'-oligoadenylate synthetase 1B (OAS1B) protein. We introduced by transgenesis the Oas1b cDNA from MBT/Pas mice carrying the R253 codon (Oas1b(MBT)) into BALB/c mice homozygous for the X253 allele (Oas1b(BALB/c)). Overexpression of Oas1b(MBT) mRNA in the brain of transgenic mice prior and in the time course of infection provided protection against the neuroinvasive WNV strain IS-98-ST1. A 200-fold induction of Oas1b(MBT) mRNA in the brain of congenic BALB/c mice homozygous for a MBT/Pas segment encompassing the Oas1b gene was also efficient in reducing both viral growth and mortality, whereas a 200-fold induction of Oas1b(BALB/c) mRNA was unable to prevent virally-induced encephalitis, confirming the critical role of the R253X mutation on Oas1b activity in live mice.


A life-threatening presentation of child physical abuse: jejunal perforation.
Intra-abdominal injuries from impacts are the second most common cause of death in battered children. However, it may be difficult to distinguish between accidental abdominal injury and abuse, especially in the absence of other clinical findings. Published reports are also limited about the diagnosis of abuse in children with intra-abdominal injury. We report a case with jejunal perforation, multiple soft tissue injuries, and occipital fracture secondary to child abuse who was initially admitted to our hospital with complaint of fever, cough, and vomiting. An exploratory laparotomy revealed perforation of the jejunum, and an end-to-end anastomosis was performed. The patient was evaluated by the hospital's child protective team to implement appropriate diagnostic and child-protective interventions, and the child was discharged home in 10 days.


Role of Th1/Th2 cytokines in the diagnosis and prognostic evaluation of ankylosing spondylitis.
Ankylosing spondylitis (AS), a progressive disease of the spine, manifests as peripheral arthritis with tendon and ligament inflammation that restricts activity. AS is a rheumatoid autoimmune disease although the rheumatoid factor is absent in patients with AS. It is characterized by inflammatory changes such as elevated levels of serum inflammatory factors. The roles of Th1 and Th2 cytokines in autoimmune diseases are well known. However, the roles of these cytokines in the diagnosis and prognosis of AS is poorly understood. The aim of this study was to investigate the roles of Th1/Th2 cytokines in the diagnosis and prognosis of AS. The BASDAI activity, BASFI functional index, BASMI measurement score, and the levels of CRP and ESR were measured during the treatment of patients with active AS. The levels of IFN-γ and TNF-α (Th1 cytokines) and IL-4 and IL-10 (Th2 cytokines) were quantified. The levels of IL-4 and IL-10 were significantly low in the serum of patients with active AS, who also had high IFN-γ and TNF-α levels compared to those in the control individuals (P < 0.05). After treatment, the levels of IL-4 and IL-10 increased while those of IFN-γ and TNF-α decreased compared to those in individuals with active AS (P < 0.05). The disease activity index correlated positively with levels of IFN-γ and TNF-α and negatively with levels of IL-4 and IL-10, but not with that of CRP or ESR. Changes in the levels of Th1/2 cytokines in patients with AS may reflect disease activity and prognosis.


On the depolarization in granular thin films: a Mueller-matrix approach.
We describe a general method to disclose the information hidden in Mueller matrices experimentally obtained from depolarizing samples. Although spectroscopic Mueller-matrix ellipsometry allows for a model-free characterization of inhomogeneous samples, i.e., independently from any assumption on the sample structure, the interpretation of the obtained results is often challenging. The proposed method combines three different decomposition techniques applied to the measured Mueller matrices in transmission and reflection of granular thin films with different thicknesses and densities. We demonstrate that the comparative analysis of the respective differential-, product-, and sum-decomposition of the Mueller matrices, together with correlation effects and the visualization as a Poincaré sphere, reveals the particular underlying physical processes of depolarization. As an example, we apply this method on granular BaSO4 thin films. This method is general and can be applied to a wide variety of intrinsically inhomogeneous materials with applications in physics, industry, biology, or medicine.


Dynamic measurement of lumbar curvature using fibre-optic sensors.
Dynamic continuous measurement of the curvature of the lumbar spine is technically difficult but could provide important information about the functions of the spine. A new measurement system using a ribbon of specifically modified fibre-optic sensors was attached to the back and used to dynamically measure lumbar surface curvature during flexion and lifting. Reliability of the collected data and comparison to a video-based system were investigated in thirteen participants for curvature of both the lower and whole lumbar spine. The coefficients of multiple correlation of repeated measurements of curvature-time curves were found to be high, 0.97-0.98, and all measurements were as reliable as data obtained by the video method (0.93-0.97). Root mean square error values were below 2.5° for the fibre-optic system. Reattachment reliability was found to be excellent (0.91-0.97) as were comparisons to a video-based method (0.84-0.95). It is concluded that the fibre-optic motion analysis system is capable of reliably measuring sagittal lumbar curvature across time and offers the ability to provide information regarding sequencing and relative motion between specific regions of the lumbar spine.


In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract.
GNF-351 is a potent aryl hydrocarbon receptor (AHR) antagonist that inhibits dioxin response element-dependent and independent activities. Here, the absorption, metabolism and in vivo AHR antagonist activity of GNF-351 were investigated. LC-MS metabolomics was used to analyse GNF-351 metabolism in vitro and in vivo. Recombinant drug-metabolizing enzymes were employed to determine the enzymes involved in GNF-351 metabolism. Analysis of target AHR genes was performed to investigate the inhibitory effects of GNF-351 towards AHR activation. Several phase I metabolites were generated after GNF-351 was incubated with microsomes from human or mouse liver and intestine, including two oxidized GNF-351 and one tri-demethylated GNF-351. Poor absorption from the intestine resulted in no detectable levels of GNF-351 in mouse serum (0-6 h) and urine (24 h) and almost all GNF-351 was found in the faeces after 24 h. Analysis of faeces further revealed all the in vitro phase I metabolites. Novel metabolites were detected, including one di-oxidized GNF-351, two oxidized and tri-demethylated GNF-351, one dehydrogenated product of oxidized GNF-351, and one sulfation product of di-oxidized GNF-351. Cytochromes P450 were demonstrated to be the major enzymes involved in metabolism of GNF-351. After oral administration to mice, GNF-351 readily inhibited β-naphthoflavone-induced AHR activation in ileum and colon, but not that in the liver. While poor absorption and extensive metabolism after oral administration limited the in vivo effects of the pure AHR antagonist GNF-351 in liver, it could be used to inhibit AHR activation in intestine and colon.


Role of CD36 in cancer progression, stemness, and targeting.
CD36 is highly expressed in diverse tumor types and its expression correlates with advanced stages, poor prognosis, and reduced survival. In cancer cells, CD36: 1) increases fatty acid uptake, reprogramming lipid metabolism; 2) favors cancer cell proliferation, and 3) promotes epithelial-mesenchymal transition. Furthermore, CD36 expression correlates with the expression of cancer stem cell markers and CD36+ cancer cells display increased stemness functional properties, including clonogenicity, chemo- and radioresistance, and metastasis-initiating capability, suggesting CD36 is a marker of the cancer stem cell population. Thus, CD36 has been pointed as a potential therapeutic target in cancer. At present, at least three different types of molecules have been developed for reducing CD36-mediated functions: blocking monoclonal antibodies, small-molecule inhibitors, and compounds that knock-down CD36 expression. Herein, we review the role of CD36 in cancer progression, its participation in stemness control, as well as the efficacy of reported CD36 inhibitors in cancer cell cultures and animal models. Overall, the evidence compiled points that CD36 is a valid target for the development of new anti-cancer therapies.


Grating-based optical scheme for the universal generation of inhomogeneously polarized laser beams.
We propose and analyze a new optical system to transform linearly polarized laser modes into axially symmetric (radial or azimuthal) modes that show more promise in various applications, as well as generating various inhomogeneously polarized configurations. The system is based on the coherent composition of modal beams with phase diffraction gratings that allow the intermode phase shift to be varied without the need for auxiliary components. What makes the system simple and universal is the use of diffractive optical elements to generate required mode patterns with specific space orientation along with the simultaneous generation of different beams with different transverse mode content, all of which can subsequently be combined.


Validation of the association of TCF7L2 and SLC30A8 gene polymorphisms with post-transplant diabetes mellitus in Asian Indian population.
The rs7903146 and rs13266634 polymorphisms in the TCF7L2 and SLC30A8 genes, respectively, have been reported to be associated with type 2 diabetes. However, little is known about the association of these polymorphisms with post-transplant diabetes mellitus (PTDM). To study this linkage, we determined a distribution of allele and genotype frequencies in Asian Indians. 42 PTDM and 98 non-PTDM subjects were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect for rs7903146 and rs13266634 polymorphisms. The clinical details and statistical analysis for PTDM and non-PTDM subjects were recorded. Our results observed higher frequencies of the minor alleles in rs7903146 and rs13266634 polymorphisms in the PTDM group compared to the non-PTDM subjects. The allele frequencies also found to be significantly associated with PTDM (rs7903146: T vs C: OR-2.6; (95%CI: 1.2-5.6); p = 0.01; rs13266634: T vs C: OR-2.0; (95%CI: 1.1-3.4); p = 0.01). These findings suggest that rs7903146 and rs13266634 polymorphisms are associated with PTDM in the Asian Indian population despite a relatively small study group.


The central role of macrophages in trypanosomiasis-associated anemia: rationale for therapeutical approaches.
Bovine African trypanosomiasis causes severe economical problems on the African continent and one of the most prominent immunopathological parameters associated with this parasitic infection is anemia. In this report we review the current knowledge of the mechanisms underlying trypanosomiasis-associated anemia. In first instance, the central role of macrophages and particularly their activation state in determining the outcome of the disease (i.e. trypanosusceptibility versus trypanotolerance) will be discussed. In essence, while persistence of classically activated macrophages (M1) contributes to anemia development, switching towards alternatively activated macrophages (M2) alleviates pathology including anemia. Secondly, while parasite-derived glycolipids such as the glycosylphosphatidylinositol (GPI) induce M1, host-derived IL-10 blocks M1-mediated inflammation, promotes M2 development and prevents anemia development. In this context, strategies aimed at inducing the M1 to M2 switch, such as GPI-based treatment, adenoviral delivery of IL-10 and induction of IL-10 producing regulatory T cells will be discussed. Finally, the crucial role of iron-homeostasis in trypanosomiasis-associated anemia development will be documented to stress the analogy with anemia of chronic disease (ACD), hereby providing new insight that might contribute to the treatment of ACD.


SARS-CoV-2 in wastewater: State of the knowledge and research needs.
The ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a Public Health Emergency of International Concern, which was officially declared by the World Health Organization. SARS-CoV-2 is a member of the family Coronaviridae that consists of a group of enveloped viruses with single-stranded RNA genome, which cause diseases ranging from common colds to acute respiratory distress syndrome. Although the major transmission routes of SARS-CoV-2 are inhalation of aerosol/droplet and person-to-person contact, currently available evidence indicates that the viral RNA is present in wastewater, suggesting the need to better understand wastewater as potential sources of epidemiological data and human health risks. Here, we review the current knowledge related to the potential of wastewater surveillance to understand the epidemiology of COVID-19, methodologies for the detection and quantification of SARS-CoV-2 in wastewater, and information relevant for human health risk assessment of SARS-CoV-2. There has been growing evidence of gastrointestinal symptoms caused by SARS-CoV-2 infections and the presence of viral RNA not only in feces of infected individuals but also in wastewater. One of the major challenges in SARS-CoV-2 detection/quantification in wastewater samples is the lack of an optimized and standardized protocol. Currently available data are also limited for conducting a quantitative microbial risk assessment (QMRA) for SARS-CoV-2 exposure pathways. However, modeling-based approaches have a potential role to play in reducing the impact of the ongoing COVID-19 outbreak. Furthermore, QMRA parameters obtained from previous studies on relevant respiratory viruses help to inform risk assessments of SARS-CoV-2. Our understanding on the potential role of wastewater in SARS-CoV-2 transmission is largely limited by knowledge gaps in its occurrence, persistence, and removal in wastewater. There is an urgent need for further research to establish methodologies for wastewater surveillance and understand the implications of the presence of SARS-CoV-2 in wastewater.


Synergistic Biomineralization Phenomena Created by a Combinatorial Nacre Protein Model System.
In the nacre or aragonite layer of the mollusk shell, proteomes that regulate both the early stages of nucleation and nano-to-mesoscale assembly of nacre tablets from mineral nanoparticle precursors exist. Several approaches have been developed to understand protein-associated mechanisms of nacre formation, yet we still lack insight into how protein ensembles or proteomes manage nucleation and crystal growth. To provide additional insights, we have created a proportionally defined combinatorial model consisting of two nacre-associated proteins, C-RING AP7 (shell nacre, Haliotis rufescens) and pseudo-EF hand PFMG1 (oyster pearl nacre, Pinctada fucata), whose individual in vitro mineralization functionalities are well-documented and distinct from one another. Using scanning electron microscopy, flow cell scanning transmission electron microscopy, atomic force microscopy, Ca(II) potentiometric titrations, and quartz crystal microbalance with dissipation monitoring quantitative analyses, we find that both nacre proteins are functionally active within the same mineralization environments and, at 1:1 molar ratios, synergistically create calcium carbonate mesoscale structures with ordered intracrystalline nanoporosities, extensively prolong nucleation times, and introduce an additional nucleation event. Further, these two proteins jointly create nanoscale protein aggregates or phases that under mineralization conditions further assemble into protein-mineral polymer-induced liquid precursor-like phases with enhanced ACC stabilization capabilities, and there is evidence of intermolecular interactions between AP7 and PFMG1 under these conditions. Thus, a combinatorial model system consisting of more than one defined biomineralization protein dramatically changes the outcome of the in vitro biomineralization process.


Acceleration of spiking neural network based pattern recognition on NVIDIA graphics processors.
There is currently a strong push in the research community to develop biological scale implementations of neuron based vision models. Systems at this scale are computationally demanding and generally utilize more accurate neuron models, such as the Izhikevich and the Hodgkin-Huxley models, in favor of the more popular integrate and fire model. We examine the feasibility of using graphics processing units (GPUs) to accelerate a spiking neural network based character recognition network to enable such large scale systems. Two versions of the network utilizing the Izhikevich and Hodgkin-Huxley models are implemented. Three NVIDIA general-purpose (GP) GPU platforms are examined, including the GeForce 9800 GX2, the Tesla C1060, and the Tesla S1070. Our results show that the GPGPUs can provide significant speedup over conventional processors. In particular, the fastest GPGPU utilized, the Tesla S1070, provided a speedup of 5.6 and 84.4 over highly optimized implementations on the fastest central processing unit (CPU) tested, a quadcore 2.67 GHz Xeon processor, for the Izhikevich and the Hodgkin-Huxley models, respectively. The CPU implementation utilized all four cores and the vector data parallelism offered by the processor. The results indicate that GPUs are well suited for this application domain.


Acute dystonia induced by neuroleptic drugs.
About 2.5% of patients treated with neuroleptic drugs develop acute dystonia within 48 h of commencing therapy. The symptoms remit on drug withdrawal or following anticholinergic therapy. Acute dystonia can also be reliably induced in many primate species by neuroleptic treatment with comparable time course, symptomatology and pharmacological characteristics to those observed in man. In general, New World monkeys appear more susceptible to acute dystonia than Old World primates. It is at present not clear whether all primates, including man, would exhibit dystonia if a sufficiently high dose of neuroleptic was administered. Alternatively, some unknown, possibly species-specific or even genetic, factors may determine an individual's susceptibility to develop dystonia. Use of a rodent model of dystonia might enable more detailed analysis of biochemical correlates of dystonic behaviour. Whilst rodents do not exhibit overt dystonic behaviour after neuroleptic treatment, they may develop oral dyskinesias which bear a close pharmacological similarity to dystonia in man and primates. However, it is not known whether chewing induced by neuroleptic drugs in rats resembles acute dystonia in primates or whether this is another movement disorder possibly unique to rodent species. The pathophysiology of acute dystonia remains unknown, but may involve striatal dopaminergic and cholinergic function. In view of the close similarity between dystonia in man and other primates, studies on the mechanisms whereby neuroleptic drugs cause acute dystonic reactions in monkeys may give some clues to the pathogenesis of spontaneous dystonia in man.


Identification of optimal reference genes in golden Syrian hamster with ethanol- and palmitoleic acid-induced acute pancreatitis using quantitative real-time polymerase chain reaction.
Acute pancreatitis (AP) is a severe disorder that leads to high morbidity and mortality. Appropriate reference genes are important for gene analysis in AP. This study sought to study the expression stability of several reference genes in the golden Syrian hamster, a model of AP. AP was induced in golden Syrian hamster by intraperitoneal injection of ethanol (1.35 g/kg) and palmitoleic acid (2 mg/kg). The expression of candidate genes, including Actb, Gapdh, Eef2, Ywhaz, Rps18, Hprt1, Tubb, Rpl13a, Nono, and B2m, in hamster pancreas at different time points (1, 3, 6, 9, and 24 h) posttreatment was analyzed using quantitative polymerase chain reaction. The expression stability of these genes was calculated using BestKeeper, Comprehensive Delta CT, NormFinder, and geNorm algorithms and RefFinder software. Our results show that the expression of these reference genes fluctuated during AP, of which Ywhaz and Gapdh were the most stable genes, whereas Tubb, Eef2, and Actb were the least stable genes. Furthermore, these genes were used to normalize the expression of TNF-α messenger ribonucleic acid in inflamed pancreas. In conclusion, Ywhaz and Gapdh were suitable reference genes for gene expression analysis in AP induced in Syrian hamster.


Sweet cues: How heparan sulfate modification of fibronectin enables growth factor guided migration of embryonic cells.
Growth factors regulate a diverse array of cellular functions including proliferation, survival, movement, and the ability to do this often involves interactions with the extracellular matrix (ECM) and particularly heparan sulfate proteoglycans (HSPGs). HSPGs have been shown to sequester growth factors, and to act as growth factor co-receptors or receptors themselves. Recent studies, however, have revealed a new role for HSPGs in mediating the interactions of growth factors with the ECM. Specifically, heparan sulfate has been shown to modulate fibronectin structure to reveal previously masked growth factor binding sites. In vivo, this mechanism appears to control the guidance of migrating cells during embryonic development as HSPG-modification of fibronectin enables direct platelet derived growth factor-fibronectin interactions necessary for this process. A model based on this observation is discussed here as well as the possibility that other growth factors/morphogens utilize similar mechanisms involving fibronectin or additional ECM proteins.


Fat dogs and coughing horses: K-12 programming for veterinary workforce development.
Workforce development strategies to educate, inform, and diversify the veterinary profession of the future must begin with children in elementary school. This article provides a description of the Fat Dogs and Coughing Horses program, which takes a multifaceted approach toward informing young students, beginning in first grade, about the interesting work and career opportunities available in the field of veterinary medicine. The program, a collaboration among Purdue University and Indiana public schools, is supported by a Science Education Partnership Award from the Office of Research Infrastructure Programs, a component of the National Institutes of Health. The overall goal of the program is to provide formal and informal educational opportunities for students, parents, teachers, and the public about the science involved in keeping people and their animals healthy. Examples of health concerns that impact both people and their pets are used to inform and excite children about careers in the health sciences. The program resulted in (1) curricula for students in Grades 1-3, 6, and 9; (2) four children's books and a set of collectible cards which highlight veterinarians, veterinary technicians, and research scientists who work with animals; and (3) four traveling museum-level quality exhibits. Preliminary assessment data has shown that the implementation of the curricula enhanced student science learning and science attitudes and interests. The program provides evidence that partnerships among professionals in veterinary medicine and K-12 education can result in impactful workforce development programs.


Mine and me: exploring the neural basis of object ownership.
Previous research has shown that encoding information in the context of self-evaluation leads to memory enhancement, supported by activation in ventromedial pFC. Recent evidence suggests that similar self-memory advantages can be obtained under nonevaluative encoding conditions, such as when object ownership is used to evoke self-reference. Using fMRI, the current study explored the neural correlates of object ownership. During scanning, participants sorted everyday objects into self-owned or other-owned categories. Replicating previous research, a significant self-memory advantage for the objects was observed (i.e., self-owned > other-owned). In addition, encoding self-owned items was associated with unique activation in posterior dorsomedial pFC (dMPFC), left insula, and bilateral supramarginal gyri (SMG). Subsequent analysis showed that activation in a subset of these regions (dMPFC and left SMG) correlated with the magnitude of the self-memory advantage. Analysis of the time-to-peak data suggested a temporal model for processing ownership in which initial activation of dMPFC spreads to SMG and insula. These results indicate that a self-memory advantage can be elicited by object ownership and that this effect is underpinned by activity in a neural network that supports attentional, reward, and motor processing.


Endogenous circadian regulation of pro-inflammatory cytokines and chemokines in the presence of bacterial lipopolysaccharide in humans.
Various aspects of immune response exhibit 24-h variations suggesting that infection susceptibility and treatment efficacy may vary by time of day. Whether these 24-h variations are endogenous or evoked by changes in environmental or behavioral conditions is not known. We assessed the endogenous circadian control and environmental and behavioral influences on ex-vivo lipopolysaccharide stimulation of whole blood in thirteen healthy participants under 48h of baseline conditions with standard sleep-wake schedules and 40-50h of constant environmental and behavioral (constant routine; CR) conditions. Significant 24-h rhythms were observed under baseline conditions in Monocyte Chemotactic Protein, Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin 8 but not Tumor Necrosis Factor alpha whereas significant 24-h rhythms were observed in all four immune factors under CR conditions. The rhythm amplitudes, expressed as a percentage of mean, were comparable between immune factors and across conditions. In contrast, the acrophase time (time of the fitted peak) was different between immune factors, and included daytime and nighttime peaks and changes across behavioral conditions. These results suggest that the endogenous circadian system underpins the temporal organization of immune responses in humans with additional effects of external environmental and behavioral cycles. These findings have implications for understanding the adverse effects of recurrent circadian disruption and sleep curtailment on immune function.


One-year effect of a supervised exercise programme on functional capacity and quality of life in peripheral arterial disease.
Peripheral arterial disease (PAD) is a chronic, progressive disease with a significant cardiovascular and cerebrovascular risk burden and a considerable impact on functional capacity and quality of life (QoL). Exercise programmes result in significant improvements in walking distances but long-term effects are uncertain. The aim of this study was to assess the one-year effects of participation in a 12-week supervised exercise programme on functional capacity and QoL for PAD patients. Patients were randomly allocated to a control (n = 16) or an exercise (n = 28) group. Data regarding functional capacity (Walking Impairment Questionnaire WIQ), disease-specific QoL (Intermittent Claudication Questionnaire ICQ) and generic QoL (SF-36) were collected at baseline, 12 weeks and 1 year. At 12 weeks, there was a trend towards improved QoL in both groups, with a tendency for greater improvement in the exercise group (p = 0.066) and a trend towards improved functional capacity (WIQ Stair-climbing p = 0.093) in the exercise group. At 1 year, ICQ scores in the exercise group were considerably better than those in the control group (p = 0.058), reflecting improved QoL and maintenance of benefits. Participation in a supervised exercise programme results in improvements in functional capacity and QoL at 1 year post-participation.


Kidney transplantation under FK 506.
The experimental immunosuppressive drug FK 506 was given to 36 renal transplant recipients, many of whom were highly sensitized. Ten were undergoing kidney retransplantation, 10 also underwent liver transplantation at an earlier time (6 patients) or concomitantly (4 patients), and 2 patients received a third organ (heart or pancreas) in addition to a liver and kidney. With follow-ups of 4 to 13 months, all but 2 of the 36 patients are alive, 29 (81%) are dialysis free, and most have good renal function. Twenty of the 29 dialysis-free patients are receiving no or low-dose (2.5 to 5.0 mg/d) prednisone therapy. Only one kidney was lost to cellular rejection. However, patients who had antidonor cytotoxic antibodies in current or historical serum samples had a high rate (3 of 9) of irreversible humoral rejection. A low incidence of posttransplant hypertension was noteworthy. Hirsutism and gingival hyperplasia were not observed. Serum cholesterol levels in patients who took FK 506 were unexpectedly low, and the effect on the level of uric acid was minimal. The side effects of FK 506 therapy include nephrotoxicity, neurotoxicity, and potential induction of a diabetic state. These are similar to the side effects of cyclosporine use, but probably less severe. The seeming safety, efficacy, and relative freedom from side effects of FK 506 encourage further trials in kidney transplantation.


Straight line repair of unilateral cleft lip: new operative method based on 25 years experience.
The resultant scar in the primary repair of unilateral cleft lip should ideally be straight and the mirror image of the philtrum on the non-cleft side. In 1993, we reported a new operative technique for unilateral cleft lip, in which we designed a straight line for the incision on the white lip. In order to produce the nostril floor, we used the white lip tissue in the area between the alar base and alveolus at the cleft side as a flap. We also used a small triangular flap above the white skin roll to prevent Cupid's peak from being drawn up. Unlike the rotation-advancement method, our technique does not leave a transverse scar at the alar base. Instead, it leaves a scar only along the line coincident with the natural philtral ridge. However, during observations of our patients, we noticed that the small triangular flap designed to be 1.5mm tended to become a conspicuous angular scar as the patients grew older. In addition, drooping of Cupid's peak on the cleft side was often observed with this small triangular flap. To make it less conspicuous, we made some modifications to the small flap above the white skin roll. With this new technique, we designed a semi-circular flap (1.5 x 3mm) above the white skin roll, instead of the small triangular flap. The suture line of our refined procedure draws a gentle curve, which looks almost straight because of skin elasticity. Moreover, the semi-circular flap causes less drooping of the upper lip than the triangular flap. We believe that revising the shape of the small flap on the white skin roll greatly improves patients' appearance. In this report, we present our refined techniques of primary repair of unilateral cleft lip.


Problems with binary gender discourse: using context to promote flexibility and connection in gender identity.
Western society recognises male and female sex from physiological attributes, such as genitals and chromosomes. 'Gender' is the social and cultural expectation of how males and females should think, behave and how they should be treated by others (Diamond, 2002). Some children and adolescents experience distress, marginalization, and abuse associated with their gender identifications, preferences and behaviours, which are inconsistent with those expected of their biological sex. Often their families and society find gender non-conformity at best difficult, at worst offensive, distressing and intolerable. There is increasing focus on how mental health professionals work with difference in gender and sexual identity and recent publications highlight the shift from pathologizing transgender to a more 'identity-based' perspective, focussing more on the stigmatizing affects of the environment and the impact on the individual (Bockting, 2009). This article describes the challenges of binary gender discourse for young people and their wider contexts and considers how clinicians may more helpfully respond to avoid unhelpful binaries and so keep the young person in mind. The therapeutic aims of the UK Gender Identity Development Service (GIDS) for children and young people are considered and examples of our work provided.


A preliminary evaluation of psychological stress amongst workers in Taiwan: a cross-sectional survey.
Stress and psychological disorders have been assigned increasing significance in the field of occupational health. Based on Japan's psychiatric disability occupational disease recognition regulation, Taiwan's Council of Labor Affairs announced "Evaluation Guidelines for psychiatric diseases induced by work-related stress" in 2009. This evaluation tool was designed to assess the source and intensity of work-related and non-work-related mental stress, and references existing Japanese guidelines. However, empirical data from workers in various sectors in Taiwan are still required to validate the utility of the guidelines. This study recruited 2319 workers from the manufacturing, service, and public administration sectors to participate in a survey between 2010 and 2011. The survey included questions regarding participants' demographic characteristics, job type or attributes, a life event stress intensity evaluation Table (35 work-related and 23 non-work-related items on a scale of 1-10). The Chinese version of the Copenhagen Burnout Inventory (C-CBI) and Chinese Health Questionnaire (CHQ-12) were also included to explore associations between work-related/non-work-related stress and health outcomes. Analyses of survey results showed events relating to employment security (e.g., "company bankruptcy" and "being fired or forced to retire" scores; mean stress intensity scores both 6.18) were the cause of the highest intensity work-related stress. Within different demographic/job type categories, women had higher stress intensity scores for most items than men (greatest difference in "sexual harassment in the workplace" score). Furthermore, executive class workers generally experienced more psychological stress than blue-collar workers (greatest difference in "serious injury or disease due to work" score). Results from regression analysis supported the observation that employees' burnout and work-related stress was more significant than non-work-related stress. Moreover, work-related/non-work-related stress intensity levels both had significant negative predictive effects on mental health. Regarding policy, this study provides empirical evidence and practical suggestions for establishing a psychological stress intensity database of workers under specific social contexts in a newly industrialized East Asian country. Such a database can be employed to help identify workers with work-related psychological disorders. Additionally, this study also provides a point of reference for enterprises to prioritize agendas when developing employee stress management and support protocols.


Quality of life of HIV-infected patients who switch antiretroviral medication due to side effects or other reasons.
The objective of this study was to investigate changes in health-related quality of life (HRQOL) among HIV patients following switch from a first- to second-line antiretroviral therapy (ART) regimen. This was an observational study of adult HIV patients in the US at 35 academic and community health centers. Patients were required to be switching an antiretroviral regimen for the first time at the enrollment visit. Patients were assigned to a study cohort based on whether the switch was due to treatment-related side effects or for any other reason as reported by their physician. Patients completed the Medical Outcomes Study-Human Immunodeficiency Virus (MOS-HIV) health survey, the Depression, Anxiety, and Stress Scale Short Form (DASS-21), and the Human Immunodeficiency Virus Treatment Satisfaction Questionnaire-status (HIVTSQs) at the enrollment visit (baseline) and a follow-up survey was completed approximately 4 weeks later. The within cohort change in survey measures from baseline to follow-up was assessed by two-sample paired t-test. Patients who switched their ART regimen due to treatment-related side effects (n = 50) had statistically significant improvements (p < .05, baseline to follow-up) in mean Physical and Mental Health Summary scores (MOS-HIV scale) and in all three HIVTSQ summary scores. Patients who switched for other reasons (n = 44) did not experience statistically significant improvements in these same measures. HIV patients whose regimen was switched due to treatment-related side effects experienced an improvement in QOL following the switch. Physicians should take the potential impact on QOL into consideration when deciding on a switch in ART regimen, particularly when patients are intolerant of their current treatment. The results are based on a patient survey and may have been influenced by recall and response bias.


Beyond body counts: a qualitative study of lives and loss in Burkina Faso after 'near-miss' obstetric complications.
Averting women's pregnancy-related death is today recognised as an international health and development priority. Maternal survival is, in this sense, a success story. There is, however, little research into what happens to the women who survive the severe obstetric complications that are the main causes of maternal mortality. This paper examines findings from repeated in-depth interviews with 64 women who survived a clinically defined 'near-miss.' These interviews were conducted as part of a prospective longitudinal study of women who 'nearly died' of pregnancy-related complications in Burkina Faso, a poor country in West Africa. Drawing on sociological and anthropological perspectives that consider the defining characteristics of 'loss' to be social as much as biomedical, the paper seeks to understand loss as disruption of familiar forms and patterns of life. Women's accounts of their lives in the year following the near-miss event show that such events are not only about blood loss, seizures or infections, but also about a household crisis for which all available resources were mobilised, with a train of physical, economic and social consequences. The paper argues that near-miss events are characterised by the near-loss of a woman's life, but also frequently by the loss of the baby and by further significant disruptions in three overlapping dimensions of women's lives. These include disruption of bodily integrity through injury, ongoing illness and loss of strength and stamina; disruption of the household economy through high expenditure, debts and loss of productive capacity; and disruption of social identity and social stability. Maternal health policy needs to be concerned not only with averting the loss of life, but also with preventing or ameliorating others losses set in motion by an obstetric crisis.


Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance.
In 150 hypercholesterolemic patients, unable to tolerate ≥1 statin because of myositis-myalgia, selected by low (<32 ng/ml) serum 25 (OH) vitamin D, we prospectively assessed whether vitamin D supplementation with resolution of vitamin D deficiency would result in statin tolerance, free of myositis-myalgia. We studied 74 men, 76 women, median age 60, 131 white, 17 black and 2 other. On no statins, 50,000 units of vitamin D was given twice a week for 3 weeks, and then continued once a week. After 3 weeks on vitamin D, statins were restarted. Patients were re-assessed on statins and vitamin D every 3 to 4 months, with serial measures of serum 25 (OH) vitamin D, creatine phosphokinase (CPK), LDL cholesterol (LDLC) and assessment of myositis-myalgia. Percentage of patients myalgia-free on vitamin D plus reinstituted statins, serum 25 (OH) vitamin D, CPK, and LDLC on reinstituted statins and concurrent vitamin D supplementation. On vitamin D supplementation plus re-instituted statins for a median of 8.1 months, 131 of the 150 patients (87%) were free of myositis-myalgia and tolerated the statins well. Serum 25 (OH) vitamin D increased from median 21 to 40 ng/ml (p < 0.001), and normalized (≥32 ng/ml) in 117 (78%) of 150 previously vitamin D deficient, statin-intolerant patients. Median LDLC decreased from 146 mg/dl to 95 mg/dl, p < 0.001. Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent serum 25 (OH) vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle causing myalgia.


Long-term survival and integration of transplanted engineered nervous tissue constructs promotes peripheral nerve regeneration.
Although peripheral nerve injury is a common consequence of trauma or surgery, there are insufficient means for repair. In particular, there is a critical need for improved methods to facilitate regeneration of axons across major nerve lesions. Here, we engineered transplantable living nervous tissue constructs to provide a labeled pathway to guide host axonal regeneration. These constructs consisted of stretch-grown, longitudinally aligned living axonal tracts inserted into poly(glycolic acid) tubes. The constructs (allogenic) were transplanted to bridge an excised segment of sciatic nerve in the rat, and histological analyses were performed at 6 and 16 weeks posttransplantation to determine graft survival, integration, and host regeneration. At both time points, the transplanted constructs were found to have maintained their pretransplant geometry, with surviving clusters of graft neuronal somata at the extremities of the constructs spanned by tracts of axons. Throughout the transplanted region, there was an intertwining plexus of host and graft axons, suggesting that the transplanted axons mediated host axonal regeneration across the lesion. By 16 weeks posttransplant, extensive myelination of axons was observed throughout the transplant region. Further, graft neurons had extended axons beyond the margins of the transplanted region, penetrating into the host nerve. Notably, this survival and integration of the allogenic constructs occurred in the absence of immunosuppression therapy. These findings demonstrate the promise of living tissue-engineered axonal constructs to bridge major nerve lesions and promote host regeneration, potentially by providing axon-mediated axonal outgrowth and guidance.


A robust brain signature region approach for episodic memory performance in older adults.
The brain signature concept aims to characterize brain regions most strongly associated with an outcome of interest. Brain signatures derive their power from data-driven searches that select features based solely on performance metrics of prediction or classification. This approach has important potential to delineate biologically relevant brain substrates for prediction or classification of future trajectories. Recent work has used exploratory voxel-wise or atlas-based searches, with some using machine learning techniques to define salient features. These have shown undoubted usefulness, but two issues remain. The preponderance of recent work has been aimed at categorical rather than continuous outcomes, and it is rare for non-atlas reliant voxel-based signatures to be reported that would be useful for modelling and hypothesis testing. We describe a cross-validated signature region model for structural brain components associated with baseline and longitudinal episodic memory across cognitively heterogeneous populations including normal, mild impairment and dementia. We used three non-overlapping cohorts of older participants: from the UC Davis Aging and Diversity cohort (n = 255; mean age 75.3 ± 7.1 years; 128 cognitively normal, 97 mild cognitive impairment, 30 demented and seven unclassified); from Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 (n = 379; mean age 75.1 ± 7.2; 82 cognitively normal, 176 mild cognitive impairment, 121 Alzheimer's dementia); and from ADNI2/GO (n = 680; mean age 72.5 ± 7.1; 220 cognitively normal, 381 mild cognitive impairment and 79 Alzheimer's dementia). We used voxel-wise regression analysis, correcting for multiple comparisons, to generate an array of regional masks corresponding to different association strength levels of cortical grey matter with baseline memory and brain atrophy with memory change. Cognitive measures were episodic memory using Spanish and English Neuropsychological Assessment Scales instruments for UC Davis and ADNI-Mem for ADNI 1 and ADNI2/GO. Performance metric was the adjusted R2 coefficient of determination of each model explaining outcomes in two cohorts other than where it was computed. We compared within-cohort performances of signature models against each other and against other recent signature models of episodic memory. Findings were: (i) two independently generated signature region of interest models performed similarly in a third separate cohort; (ii) a signature region of interest generated in one imaging cohort replicated its performance level when explaining cognitive outcomes in each of other, separate cohorts; and (iii) this approach better explained baseline and longitudinal memory than other recent theory-driven and data-driven models. This suggests our approach can generate signatures that may be easily and robustly applied for modelling and hypothesis testing in mixed cognition cohorts.


CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression.
Epithelial-mesenchymal transition (EMT) is a tightly regulated process that is critical for embryogenesis but is abnormally activated during cancer metastasis and recurrence. Here we show that a switch in CD44 alternative splicing is required for EMT. Using both in vitro and in vivo systems, we have demonstrated a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) during EMT. This isoform switch to CD44s was essential for cells to undergo EMT and was required for the formation of breast tumors that display EMT characteristics in mice. Mechanistically, the splicing factor epithelial splicing regulatory protein 1 (ESRP1) controlled the CD44 isoform switch and was critical for regulating the EMT phenotype. Additionally, the CD44s isoform activated Akt signaling, providing a mechanistic link to a key pathway that drives EMT. Finally, CD44s expression was upregulated in high-grade human breast tumors and was correlated with the level of the mesenchymal marker N-cadherin in these tumors. Together, our data suggest that regulation of CD44 alternative splicing causally contributes to EMT and breast cancer progression.


Well-to-Wheels Analysis of Zero-Emission Plug-In Battery Electric Vehicle Technology for Medium- and Heavy-Duty Trucks.
Conventional diesel medium- and heavy-duty vehicles (MHDVs) create large amount of air emissions. With the advancement in technology and reduction in the cost of batteries, plug-in battery electric vehicles (BEVs) are increasingly attractive options for improving energy efficiency and reducing air emissions of MHDVs. In this paper, we compared the well-to-wheels (WTW) greenhouse gases (GHGs) and criteria air pollutant emissions of MHD BEVs with their conventional diesel counterparts across weight classes and vocations. We expanded the Greenhouse gases, Regulated Emissions, and Energy use in Technologies (GREET) model to conduct the WTW analysis of MHDVs. The fuel economy for a wide range of MHDV weight classes and vocations, over various driving cycles, was evaluated using a high-fidelity vehicle dynamic simulation software (Autonomie). The environmental impacts of MHD BEVs are sensitive to the source of electricity used to recharge their batteries. The WTW results show that MHD BEVs significantly improve environmental sustainability of MHDVs by providing deep reductions in WTW GHGs, nitrogen oxides, volatile organic compounds, and carbon monoxide emissions, compared to conventional diesel counterparts. Increasing shares of renewable and natural gas technologies in future national and regional electricity generation are expected to reduce WTW particulate matters and sulfur oxide emissions for further improvement of the environmental performance of MHD BEVs.


Skin closure at cesarean section, polypropylene versus polyglactin 910: a randomized controlled study.
To compare the rates of surgical wound infection in women who have undergone cesarean delivery with subcuticular skin closure with polyglactin 910 or polypropylene. Between April 2018 and October 2018, patients who had undergone a cesarean delivery for any reason were randomized with polyglactin 910 or polypropylene for subcuticular skin closure. Participants were evaluated for wound complications on day 7 and 30 postoperatively. The primary outcome was surgical site infection within the first 30 days following delivery. In addition, factors affecting surgical site infections were analyzed by binary regression. A total of 220 women who had undergone cesarean delivery were randomized and 213 were included in the final analysis. The groups were similar in terms of demographic characteristics and perioperative features. No statistically significant difference was observed between the groups in terms of wound complications or superficial site infections (8.3% in the polypropylene group versus 10.6% in the polyglactin 910 group, p = .642). Similarly, no difference was observed between the groups in terms of other wound complications. A binary logistic regression analysis indicated that superficial wound site infection was not affected by gravidity, BMI, duration of operation, repeated or unplanned cesarean delivery. It was observed that surgical site infections and other wound complications in skin closures with polyglactin 910 were similar to those with polypropylene.


Controlled ileal release budesonide in pediatric Crohn disease: efficacy and effect on growth.
Although the effectiveness of controlled ileal release (CIR) budesonide in children can be extrapolated from adult studies, there are currently no data available concerning the effects of CIR budesonide therapy on linear growth. In the absence of controlled, prospective pediatric clinical trials, we reviewed the outcomes, particularly linear growth, of children and adolescents given CIR budesonide to treat active intestinal inflammation and to maintain remission. Thirty-two children (20 males) aged 14.1 +/- 2.7 years with Crohn disease of the distal ileum with or without right colon involvement were treated for active Crohn disease (baseline Pediatric Crohn Disease Activity Index, 34 +/- 14) with 9 mg daily of CIR budesonide through the Hospital for Sick Children, University of Toronto, Inflammatory Bowel Diseases program. At first follow-up visit 8.7 +/- 6.0 weeks later, 19 of 32 (59%) were judged by the physician to have responded. In the subset of 22 patients who had laboratory tests repeated at the first follow-up visit, their Pediatric Crohn Disease Activity Index fell from 33 +/- 14 to 22 +/- 16 (P = 0.001). The Pediatric Crohn Disease Activity Index score fell to less than 15 (cut-off score remission) in 29%. Six prepubertal responders continued to receive 6 mg CIR budesonide for 6 to 13 months. Five of the 6 experienced only mild or no gastrointestinal symptoms and gained weight. Nevertheless, their mean height velocity was only 2.3 +/- 1.0 cm/year, and none grew at a rate of more than 4cm/year whilst receiving CIR budesonide. These data provide grade III evidence of modest effectiveness of CIR budesonide in children with active Crohn disease confined to the ileum with or without right colon involvement. The subnormal growth observed with continued therapy is concerning and may reflect either inadequately controlled intestinal inflammation or direct suppression of linear growth, as is observed with conventional corticosteroids. Randomized controlled pediatric trials of CIR budesonide must include parameters of linear growth as an outcome variable.


The Emotion Regulation Questionnaire: Psychometric Properties in General Community Samples.
The Emotion Regulation Questionnaire (ERQ) is a 10-item self-report measure of 2 emotion regulation strategies, cognitive reappraisal and expressive suppression. It is a widely used measure of emotion regulation, but its factor structure has rarely been examined outside of university student samples, and some authors have recently questioned its factorial validity in general community samples. In this study, we examine the psychometric properties of the ERQ (original English version) in 3 Australian general community samples (N = 300, 400, 348). Confirmatory factor analyses in each sample demonstrated that the traditional 2-factor model (comprised of cognitive reappraisal and expressive suppression factors) was replicable and an excellent fit to the data. In all samples, ERQ cognitive reappraisal (α = .89-.90) and expressive suppression (α = .76-.80) scores had acceptable to excellent levels of internal consistency reliability. As expected, cognitive reappraisal scores were significantly negatively correlated with psychological distress and alexithymia, whereas expressive suppression scores were significantly positively correlated with psychological distress and alexithymia. We conclude that, similar to previous findings in student samples, the ERQ has strong psychometric properties in general community samples and can therefore be used confidently regardless of participants' student status.


Stem of SL1 RNA in HIV-1: structure and nucleocapsid protein binding for a 1 x 3 internal loop.
The 5'-leader of HIV-1 RNA controls many viral functions. Nucleocapsid (NC) domains of gag-precursor proteins select genomic RNA for packaging by binding several sites in the leader. One is likely to be a stem defect in SL1 that can adopt either a 1 x 3 internal loop, SL1i (including G247, A271, G272, G273) or a 1 x 1 internal loop (G247 x G273) near a two-base bulge (A269-G270). It is likely that these two conformations are both present and exchange readily. A 23mer RNA construct described here models SL1i and cannot slip into the alternate form. It forms a 1:1 complex with NCp7, which interacts most strongly at G247 and G272 (K(d) = 140 nM). This demonstrates that a linear G-X-G sequence is unnecessary for high-affinity binding. The NMR-based structure shows an easily broken G247:A271 base pair. G247 stacks on both of its immediate neighbors and A271 on its 5'-neighbor; G272 and G273 are partially ordered. A bend in the helix axis between the SL1 stems on either side of the internal loop is probable. An important step in maturation of the virus is the transition from an apical loop-loop interaction to a dimer involving intermolecular interactions along the full length of SL1. A bend in the stem may be important in relieving strain and ensuring that the strands do not become entangled during the transition. A stem defect with special affinity for NCp7 may accelerate the rate of the dimer transformation. This complex could become an important target for anti-HIV drug development, where a drug could exert its action near a high-energy intermediate on the pathway for maturation of the dimer.


Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme.
Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.


Tikal, Guatemala, and Emergent Maya Civilization: Excavations reveal evidence of early complex-living at a prime Maya Indian site.
It would be extravagant to claim that these pages have outlined meaningfully the early evolution of Tikal. Data have been provided largely for one excavation locus at a site which, for all its importance, merely has symptomatic value. We cannot claim to have, at present, sufficient material to document satisfyingly the conditions and products of community-wide living at any point in these early times. Present knowledge of Eb and Tzec ceramics and of all the usual archeological correlates (architecture and so on) is disturbingly incomplete. While we do have a good many data on residence throughout much of Preclassic time, considerably more information is needed before a solid evaluation of Preclassic Tikal society can be achieved. One can only hope that pending excavation programs will provide it. Yet, experience shows that probably only a tiny percentage of early cultural remains, regardless of their grandeur and importance at the time, would have survived the constant quest for construction fills to satisfy a seemingly interminable need to build and revamp.


Comparative transcriptional profiling and preliminary study on heterosis mechanism of super-hybrid rice.
Heterosis is a biological phenomenon whereby the offspring from two parents show improved and superior performance than either inbred parental lines. Hybrid rice is one of the most successful apotheoses in crops utilizing heterosis. Transcriptional profiling of F(1) super-hybrid rice Liangyou-2186 and its parents by serial analysis of gene expression (SAGE) revealed 1183 differentially expressed genes (DGs), among which DGs were found significantly enriched in pathways such as photosynthesis and carbon-fixation, and most of the key genes involved in the carbon-fixation pathway exhibited up-regulated expression in F(1) hybrid rice. Moreover, increased catabolic activity of corresponding enzymes and photosynthetic efficiency were also detected, which combined to indicate that carbon fixation is enhanced in F(1) hybrid, and might probably be associated with the yield vigor and heterosis in super-hybrid rice. By correlating DGs with yield-related quantitative trait loci (QTL), a potential relationship between differential gene expression and phenotypic changes was also found. In addition, a regulatory network involving circadian-rhythms and light signaling pathways was also found, as previously reported in Arabidopsis, which suggest that such a network might also be related with heterosis in hybrid rice. Altogether, the present study provides another view for understanding the molecular mechanism underlying heterosis in rice.


Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor.
Venous neointimal hyperplasia (NH) is the predominant cause of stenosis in hemodialysis arteriovenous grafts (AVG), but there is currently no clinically used therapy to prevent NH. A porcine AVG model was used to identify potential pharmacological targets to prevent NH. Sunitinib, a broad-spectrum tyrosine kinase inhibitor, was examined as a potential anti-NH drug utilizing in vitro and ex vivo models. In an in vivo porcine model, PDGF, VEGF and their receptors PDGFR-α and VEGFR-2 were upregulated at the venous anastomosis within 2 weeks after AVG placement, with NH development by 4 weeks. Sunitinib inhibited PDGF-stimulated proliferation, migration, phosphorylation of MAPK and PI3K/Akt proteins and changes in the expression of cell-cycle regulatory proteins in vascular smooth-muscle cells as well as VEGF-stimulated endothelial cell proliferation in vitro. In an ex vivo model, significant NH was observed in porcine vein segments perfused for 12 days under pathological shear stress. Sunitinib (100 nM) inhibited NH formation, with the intima-to-lumen area ratio decreasing from 0.45 ± 0.25 to 0.04 ± 0.02 (p < 0.05) with treatment. These findings demonstrate sunitinib to be a potential NH-preventive drug as well as the utility of an ex vivo model to investigate pharmacotherapies under pathophysiological flow conditions.


Discontinuity and disaster: gaps and the negotiation of culpability in medication delivery.
This paper shows how discontinuities in the process of drug delivery enable but also underdetermine the isolation of a culprit in adverse medication events. A case example illustrates how we are forced to abandon conceptualizations of blame that assume a dichotomy (either culpable or not), and shift instead to a more nuanced version that estimates the degree to which an actor desired, generated, or could have foreseen the harmful outcome, and the extent to which constraints external to the actor altered the event. The paper concludes that meaningful safety interventions in a system as diverse, socially embedded and complex as health care delivery cannot just build on "good science" (e.g., good methods) to generate "root" causes. Rather, they need to somehow be sensitive to how and which narratives of success and failure are created, as these constrain which countermeasures are likely to be encouraged, funded, and accepted.


Denial in myocardial infarction patients.
Since nurses are the health professionals who have the closest and most frequent contact with patients, they are in the best position to assist the MI patient with management of denial. It is important for nurses to recognize the manifestations of denial and then be able to assess the amount that denial accelerates or impedes the patient's progress toward regained health. With this increased awareness, nurses become the major influence in helping the MI patient recover psychologically as well as physically.


Sex differences in suicide incident characteristics and circumstances among older adults: surveillance data from the National Violent Death Reporting System--17 U.S. states, 2007-2009.
Each year in the U.S. more than 7,000 adults aged 60 years and older die of suicide and as the population ages, these numbers are expected to increase. While sex is an important predictor of older adult suicide, differences between males and females are often overlooked due to low occurrence, particularly among women. The National Violent Death Reporting System (NVDRS) bridges this gap by providing detailed information on older adult suicide by sex in 17 US states (covering approximately 26% of the U.S. population). NVDRS data for 2007-2009 were used to characterize male (n = 5,004) and female (n = 1,123) suicide decedents aged 60 years and older, including incident characteristics and circumstances precipitating suicide. Stratification of NVDRS data by sex shows significant differences with regard to the presence of antidepressants (19% and 45% respectively), opiates (18%, 37%), and 14 precipitating circumstances concerning mental health, interpersonal problems, life stressors and a history of suicide attempts. No differences were found for alcohol problems, suicide/other death of family or friends, non-criminal legal problems, financial problems, or disclosure of intent to take their own life. The findings of this study demonstrate the value of using comprehensive surveillance data to understand sex-specific suicide circumstances so that opportunities for targeted prevention strategies may be considered.


The perspective of patients with haemophilia with inhibitors and their care givers: preferences for treatment characteristics.
Treatment preferences of haemophilia patients with inhibitors have not been well documented. This study sought to identify treatment attributes that patients/caregivers consider most important in the USA, inasmuch as those preferences may affect patient adherence to treatment plans. A discrete choice experiment was conducted to elicit treatment preferences. Haemophilia patients with inhibitors, or their caregivers on their behalf, completed a written survey that elicited preferences for treatment features and levels synthesized from the medical literature including: risk of viral transmission, rise in inhibitor titre, reduction in thromboembolic events, number of infusions, preparation time, infusion time/volume, time required to stop bleeding/alleviate pain, use of prophylaxis, use of major surgery and medication cost. Relative importance (RI) of preferences was modelled using a multinomial logit function. Most respondents were male (49 of 51, 96.1%); mean age, 20.7 years (SD = 18.8) and 88.5% of patients had haemophilia type A. The three most important patient-identified treatment attributes were as follows: time required to stop bleeding (RI = 19.3), possibility that the level of inhibitor may rise (RI = 14.3) and risk of contracting a virus from the product (RI = 13.5). Haemophilia patients with inhibitors and their caregivers appear to be willing to accept treatments that may be more inconvenient and painful as long as the treatments are effective in quickly controlling bleeds, do not increase inhibitor levels and do not pose a risk for viral contraction. Study findings provide meaningful input to the clinical community from patients and caregivers and support the importance of physicians understanding their patients' treatment preferences.


Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%). Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).